Interleukin-1 refers to two proteins (IL1.alpha. and IL1.beta.) which play a key role early in the inflammatory response for a review see C. A. Dinarello, Blood, 87:2095-2147 (1996) and references therein!. Both proteins are made as 31 kDa1 intracellular precursor proteins which are cleaved upon secretion to yield mature carboxy-terminal 17 kDa1 fragments which are biologically active. In the case of IL-1.beta., this cleavage involves an intracellular cysteine protease, known as ICE, which is required to release the active fragment from the inactive precursor. The precursor of IL-1.alpha. is active.
These two proteins act by binding to cell surface receptors found on almost all cell types and triggering a range of responses either alone or in concert with other secreted factors. These range from effects on proliferation (e.g., of fibroblasts, T cells), apoptosis (e.g., A375 melanoma cells), cytokine induction (e.g., of TNF, IL1, IL8), receptor activation (e.g., E-selectin), eicosanoid production (e.g., PGE2) and the secretion of degradative enzymes (e.g., collagenase). To achieve this, IL-1 activates transcription factors such as NF-.kappa.B and AP-1. Several of the activities of IL-1 action on target cells are believed to be mediate through activation of kinase cascades that have also been associated with cellular stresses, such as the stress activated MAP kinases JNK/SAPK and p38.
A third member of the IL-1 family was subsequently discovered which acts as a natural antagonist of IL-1.alpha. and IL-1.beta. by binding to the IL-1 receptor but not transducing an intracellular signal or a biological response. The protein was called IL-1ra (for IL-1 receptor antagonist) or IRAP (for IL-1 receptor antagonist protein). At least three alternatively spliced forms of IL-1ra exist: one encodes a secreted protein, and the other two encode intracellular proteins. The relative role of the three forms and reason for their different localization is not known. All three proteins, IL-1.alpha., IL-1.beta. and IL-1ra, share approximately 25-30% amino acid identity and a similar three-dimensional structure consisting of twelve .beta.-strands folded into a .beta.-barrel, with an internal thrice repeated structural motif.
There are three known IL-1 receptor subunits. The active receptor complex consists of the type I receptor and IL1RAcP (for IL-1 accessory protein). The type I receptor is responsible for binding of the three ligands, and is able to do so in the absence of the IL1RAcP. However, signal transduction requires interaction of IL-1.alpha. or .beta. with the IL1RAcP. IL-1ra does not interact with the IL-1RAcP and hence cannot signal. A third receptor subunit, the type II receptor, binds IL-1.alpha. and IL-1.beta. but cannot signal due to its lack of an intracellular domain. Rather, it acts as a decoy, either in its membrane form or as an antagonist in a cleaved secreted form, and hence inhibits IL-1 activity. It only weakly binds IL-1ra.
Many studies using IL-1ra, soluble IL-1R derived from the extracellular domain of the type I IL-1R, antibodies to IL-1.alpha. or .beta., and transgenic knockouts of these genes have shown conclusively that the IL-1s play a key role in a number of pathophysiologies (see C. A. Dinarello, Blood 87:2095-2147 (1996) for a review). For example, IL-1ra has been shown to be effective in animal models of septic shock, rheumatoid arthritis, graft versus host disease, stroke, cardiac ischemia, and is currently in clinical trials for some of these indications. Moreover, IL-1.alpha. and .beta. have shown some potential as hematopoietic stem cell stimulators with potential as radio- and chemoprotectants.
More recently, a more distant member of the IL-1 family was identified. This protein, originally isolated through its ability to induce Interferon gamma in T cells and hence called Interferon gamma inducing factor (IGIF) H. Okamura et al., Nature 378:88-91 (1995)!, was subsequently shown to fold in a similar structure to the IL-1s and share weak amino acid identity Bazan et al., Nature 379-591 (1996)!. The name IL-1.gamma. was proposed, but the name IL-18 has been officially adopted. IGIF appears to play a direct role in the liver damage which occurs during toxic shock and is, therefore, like the other IL-1s in playing an early role in inflammatory and stressful conditions.
This indicates that the Interleukin-1family has an established, proven history as therapeutical targets. Clearly there is a need for identification and characterization of further members of Interleukin-1 family which can play a role in preventing, ameliorating or correcting dysfunctions or diseases, including, but not limited to, chronic and acute inflammation, arthritis, septicemia, autoimmune diseases (e.g. inflammatory bowel disease, psoriasis), transplant rejection, graft versus host disease, infection, stroke, ischemia, acute respiratory disease syndrome, restenosis, brain injury, AIDS, bone diseases (e.g. osteoporosis), cancer (e.g. lymphoproliferative disorders), atherosclerosis, and Alzheimer's disease.